This invention broadly relates to heterocyclic carbon compounds having drug and bio-affecting properties. More particularly, the invention concerns novel purine derivatives which have non-adrenergic smooth muscle relaxant properties making them particularly valuable in overcoming acute bronchospasm and as adjuncts in symptomatic management of chronic, obstructive pulmonary diseases (e.g., asthma, bronchitis, emphysema). It is also concerned with therapeutic methods and compositions employing one or more of the instant compounds as active ingredients.
Regarding types of non-adrenergic bronchodilators, the theophylline groups of xanthine derivatives are particularly prominent. For instance, aminophylline, the ethylenediamine salt of theophylline, is an effective bronchodilator which may be administered parenterally, orally, or rectally and is useful in patients where direct relaxation of bronchial muscle is desired. Notwithstanding widespread use, the xanthine class of non-adrenergic bronchodilators have major disadvantages with respect to gastric irritation, cardiovascular and central nervous system side effects. Thus, there is a need for new and effective bronchodilators which increased potency and/or fewer or reduced untoward effects. As shown by standard pharmacological tests, representative compounds of the instant invention have nonadrenergic bronchodilating activity with minimal cardiovascular and central nervous system side effects.
The basic purine nucleus contains a six-membered pyrimidine ring fused to the five-membered imidazole ring as shown in the following plane formula with the numbering system used herein noted. ##STR1## Various types of purine derivatives are known in which the parent purine is substituted at one or more of positions 2, 6, and 9 as illustrated in the following references.
1. J. A. Montgomery, et al., J. Am. Chem. Soc., 80, 409-411 (1958) describe adenine derivatives of the formula ##STR2## wherein R is n-butyl, cyclopentyl and cyclohexyl as potential anti-cancer agents.
2. H. J. Schaeffer, et al., J. Am. Chem. Soc., 81, 197-201 (1959) describe synthesis of compounds having the formula ##STR3## wherein R is 2-hydroxycyclohexyl or 2-cyclohexenyl as potential anti-cancer agents.
3. U.S. Pat. No. 3,917,837 (Lin, et al.) discloses the use of the compound ##STR4## as an anti-inflammatory agent.
4. U.S. Pat. No. 3,862,189 (Schwender) concerns compounds of the formula ##STR5## wherein, inter alia, R.sub.1 is amino, alkylamino, aralkylamino, etc.; and R.sub.2 is di-substituted phenylalkyl, tetrahydroquinoylalkyl, etc. useful as antianginal or bronchodilator agents.
5. U.S. Pat. No. 3,930,005 (Wojnar, et al.) discloses compounds of the formula ##STR6## wherein R.sub.1 is hydrogen, halogen, lower alkyl, lower alkoxy, amino, lower alkylamino or di-lower alkylamino and R.sub.2 and R.sub.3 may be hydrogen or lower alkyl as possessing anti-inflammatory activity.
6. R. Marumoto, et al., Chem. Pharm. Bull., 23(4), 759-774 (1975) describe, inter alia, compounds of the formula ##STR7## wherein R is (lower)alkyl. The compounds are said to have coronary vasodilating activity.
7. Belgian Pat. No. 853,086 (Farmdoc 70719Y) discloses compounds of the formula ##STR8## wherein either X is C.sub.1 -C.sub.6 alkoxy or --NHR; R is H or (lower)alkyl; Y is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.10 cycloalkyl or hydroxycycloalkyl, phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbons, or --AR.sup.1 ; A is methylene or ethylene; R.sup.1 is phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbons; Q is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.10 cycloalkyl or hydroxycycloalkyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbons, phenyl, halophenyl, trifluoromethyl-phenyl or AR.sup.1 ; or X is halogen or (lower)dialkylamino; Y is methyl, ethyl, cyclopentyl, phenyl, halophenyl, trifluoromethyl-phenyl or benzyl and Q is as previously defined. The compounds are reported to be useful in treating psoriasis.